Canadian Adverse Reaction Newsletter, Volume 24 - Issue 3 –July 2014

ISSN 1499-9447
Cat no H42-4/1-24-3E

Health Products and Food Branch
Marketed Health Products Directorate
Canadian Adverse Reaction Newsletter Editorial Team

In this Issue

Scope

This quarterly publication alerts health professionals to potential signals detected through the review of case reports submitted to Health Canada. It is a useful mechanism to stimulate adverse reaction reporting as well as to disseminate information on suspected adverse reactions to health products occurring in humans before comprehensive risk-benefit evaluations and regulatory decisions are undertaken. The continuous evaluation of health product safety profiles depends on the quality of your reports.

Reporting Adverse Reactions
Canada Vigilance Program
Phone: 1-866-234-2345
Fax: 1-866-678-6789

For more information on how to report an adverse reaction, visit the Reporting Adverse Reactions to Drugs and Other Health Products page.

Caveat: Adverse reactions (ARs) to health products are considered to be suspicions, as a definite causal association often cannot be determined. Spontaneous reports of ARs cannot be used to estimate the incidence of ARs because ARs remain underreported and patient exposure is unknown.

Some of the hyperlinks provided are to sites of organizations or other entities that are not subject to the  
. The material found there is therefore in the language(s) used by the sites in question.

Cisplatin and aortic thrombosis

Key points

  • Six Canadian cases of aortic thrombosis have been reported in cancer patients after initiation of treatment with cisplatin, in addition to 15 published international cases.
  • In many of these patients, the condition stabilized or resolved after initiation of anticoagulation therapy or surgery.
  • Early detection and management of aortic thrombosis increases the chances of a favourable outcome.

Cisplatin, a platinum agent, is a DNA-modifying anticancer drug that has been marketed in Canada since 1979. It is indicated for the treatment of genitourinary cancers including cancers of the testis, bladder and ovary.Reference 1,Reference 2,Reference 3,Reference 4,Reference 5

Aortic thrombosis is a rare and potentially life-threatening disorder characterized by the formation of a clot in the aorta. It rarely occurs spontaneously in such large vessels without the presence of atherosclerotic plaques.Reference 6,Reference 7 Aortic thrombosis may be related to concomitant hereditary or acquired hypercoagulable states, as well as to factors that promote clot formation (e.g., cancer, pregnancy, recent surgery, trauma, immobility, use of certain medications or substances, sepsis, polycythemia, autoimmune disease, inflammation of the blood vessels, smoking, etc.).Reference 6,Reference 7

As of April 30, 2014, 6 Canadian cases of aortic thrombosis in cancer patients after treatment initiation with cisplatin were reported to Health Canada, including 5 published cases (Reference Table 1).Reference 8,Reference 9 The most recent Canadian case occurred in 2011.

Of the 6 Canadian cases, 5 indicated that the patient was treated with anticoagulants and one required surgery (thrombectomy of the aorta and aortobifemoral grafts in one case). In 3 cases, the thrombus was detected after the last dose of cisplatin. The status of cisplatin treatment continuation is unknown for the remaining cases. Potential confounding factors for aortic thrombosis in these cases included a higher coagulation state associated with the underlying malignancy and other known predisposing factors such as smoking (reported in 4 cases), obesity (noted in one case), and previous history of vascular disease (transient ischemic attacks noted in one case). Fifteen additional international cases reporting the occurrence of aortic thrombosis after initiation of treatment with cisplatin were identified in the literature from 13 publications.Reference 7,Reference 10,Reference 11,Reference 12,Reference 13,Reference 14,Reference 15,Reference 16,Reference 17,Reference 18,Reference 19,Reference 20,Reference 21

Table 1: Summary of Canadian reports of aortic thrombosis after initiation of treatment with cisplatin submitted to Health Canada as of April 30, 2014 Reference *
Case Age/sex Suspect health products Indication Clisplatin dose at each chemotherapy cycle Duration of exposure prior to detection Outcome
Reference *These data cannot be used to determine the incidence of adverse reactions (ARs) because ARs are underreported and neither patient exposure nor the amount of time the drug was on the market has been taken into consideration.
1Reference 8 60/F Cisplatin, fluorouracil,
leucovorin, oxaliplatin
Recurrent rectosigmoid adenocarcinoma 100 mg/m2 IV, on day 1 6 days after end of 3rd cycle Stable thrombus at 12 months
2Reference 8 53/M Cisplatin,
etoposide
Small cell lung adenocarcinoma 20 mg/m2 IV, on days 1 to 3 4 days after end of 3rd cycle Death (10 days after initiation of anticoagulants)
3Reference 8 53/M Cisplatin, vinorelbine Lung adenocarcinoma 75 mg/m2 IV, on day 1 14 days after end of 4th cycle Stable thrombus at 9 months
4Reference 8 50/F Cisplatin, vinorelbine Non-small cell lung cancer 75 mg/m2 IV, on day 1 14 days after end of 4th cycle Resolved (complete resolution at 6 months)
5 57/M Cisplatin Bladder cancer Not reported 7 days after end of 3rd cycle Unknown
6Reference 9 54/F Cisplatin, etoposide Metastatic large-cell lung cancer 75 mg/m2 IV, on day 1 Second cisplatin cycle was completed (no other information provided) No recurrence more than 2 years after thrombectomy

The product monographs for cisplatin do not list aortic thrombosis.Reference 1,Reference 2,Reference 3,Reference 4,Reference 5 However, they indicate that cases of clinically heterogeneous vascular toxicities coincident with the use of cisplatin in combination with other antineoplastic agents have been reported rarely. These events may include myocardial infarction, cerebrovascular accident, thrombotic microangiopathy (hemolytic uremic syndrome), and cerebral arteritis. The exact mechanism for the occurrence of vascular toxicities with cisplatin is unclear.

Health care professionals are reminded that aortic thrombosis has been observed in patients under treatment with cisplatin. Early detection of aortic thrombosis may help to improve prognosis.Reference 17 Health care professionals are encouraged to report to Health Canada any cases of aortic thrombosis suspected of being associated with cisplatin.

David Duguay, PhD; Josephine Djulus, MD; Pascale Springuel, BPharm, DESS, Health Canada

Hydroxychloroquine and hypoglycemia

Background:

Hydroxychloroquine (Plaquenil) is indicated for the treatment of rheumatoid arthritis, discoid and systemic lupus erythematosus, and malaria (acute attacks and suppressive treatment).1, Reference *

Hypoglycemia is generally defined by (a) the presence of symptoms consistent with hypoglycemia; (b) a low plasma glucose level (the lower limit of the fasting plasma glucose level is normally approximately 3.9 mmol/L); and (c) the relief of those symptoms after the plasma glucose level is raised.Reference 2 Clinical manifestations of hypoglycemia include neuroglycopenic symptoms (e.g., confusion, fatigue, seizure, loss of consciousness, and if hypoglycemia is severe and prolonged, death) and neurogenic symptoms (e.g., sweating, hunger, palpitations, trembling, anxiety, etc.).  Hypoglycemia is rare in the absence of antidiabetic therapy.

Summary:

The potential for hydroxychloroquine to enhance the hypoglycemic effects of antidiabetic agents is known.Reference 1 As of Dec. 31, 2013, Health Canada received 2 reports of hypoglycemia suspected of being associated with hydroxychloroquine. Both reports describe the reaction as occurring in the context of co-administration with insulin or metformin.

However, hypoglycemia involving hydroxychloroquine without co-administration of a hypoglycemic agent has been reported in the literature.Reference 3,Reference 4,Reference 5 There is sufficient evidence to support a causal association between hydroxychloroquine use and the onset of hypoglycemia in this context, including serious cases involving a loss of consciousness and hospitalization.

Next steps:

Health care professionals should be aware of the association between hypoglycemia and hydroxychloroquine, with or without the concomitant use of antidiabetic agents. The Canadian product monograph for Plaquenil now includes the risk of hypoglycemia under the Warnings and Precautions section.Reference 1

  • Patients treated with hydroxychloroquine should be warned about the risk of hypoglycemia and the associated clinical signs and symptoms so that they may be recognized and addressed.
  • Patients presenting with symptoms suggestive of hypoglycemia should have their blood glucose level checked and the need for hydroxychloroquine treatment reviewed as necessary.
  • In cases of severe hypoglycemia, hydroxychloroquine treatment should be discontinued and an alternative therapy considered.
  • If patients use hydroxychloroquine concomitantly with antidiabetic agents, a decrease in dose of insulin or antidiabetic drugs may be required.

David Duguay, PhD, Health Canada

Case Presentation

Recent Canadian cases are selected based on their seriousness, frequency of occurrence or the fact that the reactions are unexpected. Case presentations are considered suspicions and are presented to stimulate reporting of similar suspected adverse reactions.

Suspected interaction between ginkgo biloba and efavirenz

Health Canada received a published case report of a potential drug-herb interaction between efavirenz (Sustiva) and a ginkgo biloba product. Efavirenz is a selective non-nucleoside reverse transcriptase inhibitor that is indicated for the treatment of HIV-1 infection in combination with other antiretroviral (ARV) agents. It is known to interact with various medications, foods and natural health products (NHPs).

The case involved a 41-year-old HIV-infected man on ARV therapy consisting of zidovudine, lamivudine and efavirenz, with good viral suppression (< 50 copies/mL) for 10 years.Reference 1 Routine blood work detected a rise in the patient’s HIV viral load (to 1350 copies/mL).  Upon questioning, he denied any missed doses but revealed the daily use of NHPs including omega-3 fatty acid, calcium, magnesium, vitamin D, a multivitamin, flax oil, rutin, and 300 mg of an unspecified ginkgo biloba product per day for the previous 2 months. Additionally, he used horse chestnut periodically for hemorrhoids treatment.

After discontinuation of the ginkgo biloba product and horse chestnut, the patient’s HIV was re-suppressed by the same ARV therapy one month later. Based on a previous published case report, a similar drug-herb interaction between ginkgo biloba and efavirenz was suspected.Reference 2

People living with HIV/AIDS often use a combination of prescription and non-prescription health products, including NHPs.  Health care professionals are encouraged to remind patients to disclose the use of all health products, including non-prescription drugs and NHPs. Drug-NHP interactions may lead to serious adverse reactions and/or a reduction in the drugs’ intended benefits.

Health Canada encourages the reporting of all suspected cases of interactions, including those that occur with the use of pharmaceuticals, NHPs, and food products to the Canada Vigilance Program.

Quarterly Summary of health professional and consumer advisories

Health professional and consumer advisories posted between February 25 and May 26, 2014
DateReference * Product Subject
Reference *Date of issuance. This date may differ from the posting date.
May 23 Heartland Natural Wild Yam Moisturizing Cream Contains undisclosed prescription drug ingredient
May 23 PMS-Losartan-HCTZ Recall: labelling error in one lot
May 16 Hospira Sodium Chloride 0.9% Irrigation, USP, 3000 mL flexible container Recall: potential leakage of bags in one lot
May 16 Lite Fit USA One lot recalled in the U.S.
May 14 Serotonin blocking drugs used to treat nausea and vomiting Risk of serotonin syndrome
May 13 “Thyroid Gland” No longer authorized for sale
May 13 Surgical mesh Complications associated with transvaginal implantation
May 9 Biolyse Pharma Corporation License suspended due to serious manufacturing concerns
May 9 Peace Naturals Project Inc. marijuana for medical purposes Recall: positive bacterial testing outside of acceptable limits for one batch
May 7 Laparoscopic electric morcellators Risk of spread of unsuspected uterine sarcoma
May 7 Temodal (temozolomide) Risk of liver problems
Apr 22 & 25 Benlysta (belimumab) Reports of progressive multifocal leukoencephalopathy
Apr 18 Greenleaf Medicinals marijuana for medical purposes Recall: issues with the company’s production practices which may impact one batch
Apr 17 Clinimix - 5% Travasol Amino Acid Injection with Electrolytes in 16.6% Dextrose Injection, 1 L Recall: particulate matter found in the solution
Apr 11 Unauthorized health products Seizure from "SVN FUEL" stores in BC
Apr 10 Neupogen (filgrastim) and Neulasta (pegfilgrastim) Risk of capillary leak syndrome
Apr 9 & 14 Amplatzer Septal Occluder Risk of erosion
Apr 9 Cefazolin for Injection USP 1g Potential for longer reconstitution time and precipitation of the reconstituted solution
Apr 9 "L-Showm Weight Loss Pills" Seizure of unauthorized health product from U-Box store in Burnaby, BC
Apr 7 Busulfex (busulfan) 6 mg/mL Injection Potential for particulate matter in 10 mL vials
Apr 7 Zelboraf (vemurafenib) Liver problems
Apr 5, 9 & 23 NaturaLyte Sodium Bicarbonate Liquid Concentrate Recall: risk of bacterial contamination
Mar 28 Remeron / Remeron RD (mirtazapine) Abnormal heart rhythms
Mar 26 Imuran (azathioprine) or Purinethol (mercaptopurine) Hepatosplenic T-cell lymphoma
Mar 26 Emergency contraceptive pills New warnings about reduced effectiveness in women over a certain body weight
Mar 13 Hospira infusion pumps New intravenous pumps still unavailable due to ongoing design and quality concerns
Mar 11 Abbott FreeStyle glucose test strips May produce false test results with certain devices
Feb 27 Herbal detox and laxative products "Formule L1" and "Detox Spring-Fall" Recall: important risk information missing from label
February 25 to May 26 Foreign products 14 Foreign Product Alerts (FPAs) were posted during this period

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Canadian Adverse Reaction Newsletter

Health Canada
Marketed Health Products Directorate
Address Locator 0701D
Ottawa ON K1A 0K9
Telephone: 613-954-6522
Fax: 613-952-7738

Editorial Team
Patricia Carruthers-Czyzewski, BScPhm, MSc (Editor-in-Chief)
Christianne Scott, BPharm, MBA
Jared Cousins, BSP
Hoa Ly, BSc
Emir Al-Khalili, RPh, BScPhm, MSc
Nicoleta Hosszu Ungureanu, MSc

Acknowledgement
We thank Sally Pepper, RPh, BScPhm for her participation in the production of the newsletter.

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Reporting Adverse Reactions
Canada Vigilance Program
Telephone: 1-866-234-2345
Fax: 1-866-678-6789

Copyright
© 2014 Her Majesty the Queen in Right of Canada. This publication may be reproduced without permission provided the source is fully acknowledged. The use of this publication for advertising purposes is prohibited. Health Canada does not assume liability for the accuracy or authenticity of the information submitted in case reports.

Due to time constraints relating to the production of this publication, information published may not reflect the most current information.

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